Interstitial cystitis (IC) is a disease defined primarily by irritative voiding symptoms of uncertain etiology and pathogensis. One of the long term goals of this project is to define pathogenic processes responsible for the symptoms of IC. Only after these processes are identified can investigation of potential etiologic mechanisms responsible for these pathogenic processes begin. The symptoms of IC are similar to other conditions such as bacterial cystitis, tuberculosis cystitis, radiation cystitis, cyclophosphamide cystitis or other chemical cystitis , bladder calculi and bladder tumors particularly carcinoma in situ. Therefore the bladder reacts to quite different forms of insult with the same stereotypic symptoms of urgency, frequency, nocturia and bladder pain. Thus the symptoms if IC may results from several different pathogenic processes in different patients all causing the same stereotypic symptom complex. In order to address this, animal experiments and clinical studies are described to investigate several divergent potential pathogenic processes that could be responsible for IC symptoms as denoted in the following hypotheses: Hypothesis 1: The sensory innervation of the IC bladder is aberrant. Hypothesis 2: Bladder neuropeptide abnormalities are a consequence of increased bladder most cell activation. Hypothesis 3: Specific substances in IC urine may induce symptoms directly or indirectly through increased bladder permeability or normal urinary constituents may induce symptoms as a result of an intrinsically leaky IC bladder urothelium. Hypothesis 4: A population of IC patients are suffering from an occult bladder infection produced by fastidious organisms that go undetected by routine culture methods. The project proposes to investigate the distribution of a panel of neuropeptide antibodies in normal and IC bladder as well as bladder, dorsal root ganglion and spinal cord of 2 different animal models: The guinea pig model of chronic mast cell activation and the rabbit bladder model of chronic intravesical IC patients and to determine whether there is any constituent in IC urine that induces animal bladders to become more permeable. Microbiologic studies are also described to detect patients suffering from an infection by organisms that do not grow easily in the routine culture media used in clinical microbiology. It is anticipated that at the conclusion of this project period the majority of IC patients will be able to be classified into distinct pathogenic profiles.